EP2816039B1 - Verfahren zur herstellung eines linezolidzwischenprodukts - Google Patents

Verfahren zur herstellung eines linezolidzwischenprodukts Download PDF

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Publication number
EP2816039B1
EP2816039B1 EP13749142.9A EP13749142A EP2816039B1 EP 2816039 B1 EP2816039 B1 EP 2816039B1 EP 13749142 A EP13749142 A EP 13749142A EP 2816039 B1 EP2816039 B1 EP 2816039B1
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Prior art keywords
process according
fluoro
linezolid
morpholinophenyl
mixture
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French (fr)
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EP2816039A4 (de
EP2816039A1 (de
Inventor
Fuli Zhang
Chunbo YANG
Bin Liang
Pengcheng QIU
Hairong Luo
Jiang Li
Jian CHAI
Qingfeng CAI
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Shanghai Institute of Pharmaceutical Industry
Zhejiang Hisun Pharmaceutical Co Ltd
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Shanghai Institute of Pharmaceutical Industry
Zhejiang Hisun Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel process for preparing a pharmaceutical intermediate. Specifically, it relates to a novel synthetic process of a key intermediate, a methyl substitute of (S)-2-(3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) (I), which is involved in the process of synthesizing an antibiotic, i.e., linezolid.
  • Linezolid is a novel oxazolidinone-type antibiotic, which is developed by Pharmacia & Upjohn Company (P&U).
  • Linezolid takes effect on the ribosome of bacteria, and inhibits the synthesis of bacterial protein.
  • Linezolid is mainly used in the treatment of bacteremia caused by vancomycin-resistant enterococci (VRE), pneumonia and complicated skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA), and bacteremia caused by penicillin resistant Streptococcus pneumonia (PRSP).
  • VRE vancomycin-resistant enterococci
  • MRSA methicillin-resistant Staphylococcus aureus
  • PRSP penicillin resistant Streptococcus pneumonia
  • a methyl substitute of (S)-2-(3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) is the key intermediate in the synthesis of linezolid, wherein the structure is as shown in Formula (I).
  • Linezolid can be obtained by treating the intermediate with a deprotective agent followed by acetylation.
  • the yield of the first step in this route is relatively low, and an inversion of configuration might easily happen.
  • the ratio of products to isomers is about 85:15, wherein the isomers are difficult to separate and will be brought into the subsequent reactions till the final product (i.e., linezolid), thereby affecting the product quality.
  • WO 2011/137222 A1 discloses a further process and intermediates for preparing linezolid, and pharmaceutically acceptable salts thereof.
  • WO 02/32857 A1 discloses methods of preparing pharmacologically active oxazolidinones and various intermediates used in the method.
  • the technical problem to be solved by the present invention is to overcome the defects in the present processes for preparing linezolid, such as severe conditions, high requirements for the equipment, a potential safety hazard, low yields, difficulty in separating the by-products, high costs, complex processes, and not suitable for an industrial production, etc.
  • the present invention provides a novel process according to claim 1 of preparing the key intermediate (I) which is suitable for an industrial production.
  • This process comprises the following steps:
  • the compound of Formula (I) is obtained by a cyclization reaction of 3-fluoro-4-morpholinophenyl isocyanate (II) and epoxy compound (III) in the presence of a reaction solvent and a catalyst.
  • R group is a protected amino group.
  • protected used herein has a common meaning known in the art. That is, in order to prevent a group from being broken by a reaction, the group is firstly protected, and then deprotected after the reaction completes.
  • the R group is: and the whole structure (I-1) is as follows:
  • linezolid can be prepared by subsequent reactions as follows:
  • the catalyst used in the cyclization reaction of the present invention is a Lewis acid or a mixture thereof, wherein the Lewis acid includes but not limited to lithium bromide, magnesium bromide, lithium chloride, magnesium chloride, magnesium iodide, lithium iodide, lithium chloride, zinc chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, or a mixture thereof, preferably lithium bromide, magnesium bromide, magnesium iodide and the like, or any mixture thereof.
  • the solvent used in the cyclization reaction of the present invention is an aprotic solvent or a mixture thereof, wherein the aprotic solvent includes but not limited to ethyl acetate, butyl acetate, isoamyl acetate, toluene, xylene, chlorobenzene, tetrahydrofuran, dichloromethane, N,N- dimethylformamide, C 6 -C 8 alkanes, acetone, 1,4-dioxane, acetonitrile or a mixture thereof, preferably butyl acetate, xylene, N,N -dimethylformamide, tetrahydrofuran and the like, or any mixture thereof.
  • the aprotic solvent includes but not limited to ethyl acetate, butyl acetate, isoamyl acetate, toluene, xylene, chlorobenzene, tetrahydrofuran, dichloromethane,
  • the temperature of the cyclization reaction in the present invention is 60 °C-150 °C, preferably 100-140 °C, particularly preferably 115-125 °C.
  • the present invention has the following advantages: the improved process is simple, the reaction is mild, the total yield is high, the product has good purity, and it does not require the utilization of hazardous agents (such as, butyl lithium, sodium azide) as well as it does not require severe conditions (such as ultra-low temperatures, etc.).
  • hazardous agents such as, butyl lithium, sodium azide
  • severe conditions such as ultra-low temperatures, etc.
  • the present invention is further illustrated by but not limited to the following examples.
  • the compound 3-fluoro-4-morpholinophenyl isocyanate (II) can be prepared by the process described in Chinese Journal of Medicinal Chemistry, pages 287-289, 20 (4), 2010 .
  • the compound (III) and the similar structure compounds thereof can be prepared by the method disclosed in EP1403267 .
  • Example 1 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione (I-1).
  • Example 2 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.
  • Example 3 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.
  • Example 4 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.
  • Example 5 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.
  • Example 6 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.
  • Example 7 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.
  • Example 8 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.
  • Example 9 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.
  • Example 10 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.
  • Example 11 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.
  • Example 12 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.
  • Example 13 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (11)

  1. Verfahren zum Herstellen von einem Zwischenprodukt von Linezolid, das die Formel (I) aufweist:
    Figure imgb0021
     wobei das Verfahren die folgenden Schritte umfasst:
    Figure imgb0022
     eine Cyclisierungsreaktion, die von 3-Fluor-4-morpholinophenylisocyanat (II) und einer Epoxyverbindung (III) durchgeführt, um die Verbindung mit der Formel (I) zu erhalten,
    wobei R eine geschützte Aminogruppe ist, die wie folgt ist:
    Figure imgb0023
  2. Verfahren nach Anspruch 1, wobei die Cyclisierungsreaktion in Gegenwart eines Katalysators durchgeführt wird, wobei der Katalysator vorzugsweise eine Lewis-Säure oder eine Mischung daraus ist.
  3. Verfahren nach Anspruch 2, wobei der Katalysator aus Lithiumbromid, Magnesiumbromid, Lithiumchlorid, Magnesiumchlorid, Magnesiumiodid, Lithiumiodid, Lithiumchlorid, Zinkchlorid, Tetra-n-butylammoniumbromid, Tetra-n-butylammoniumchlorid oder irgendeiner Mischung daraus ausgewählt ist.
  4. Verfahren nach Anspruch 2 oder Anspruch 3, wobei der Katalysator aus Lithiumbromid, Magnesiumbromid, Magnesiumiodid oder irgendeiner Mischung daraus ausgewählt ist.
  5. Verfahren nach einem der Ansprüche 1-4, wobei die Cyclisierungsreaktion in einem Lösungsmittel durchgeführt wird, wobei das Lösungsmittel vorzugsweise ein aprotisches Lösungsmittel oder eine Mischung daraus ist.
  6. Verfahren nach Anspruch 5, wobei das aprotische Lösungsmittel Petroleumether, Ethylacetat, Isoamylacetat, Butylacetat, Toluol, Xylen, Chlorbenzen, Tetrahydrofuran, Dichlormethan, N,N-Dimethylformamid, C6-C8 Alkane, Aceton, 1,4-Dioxan, Acetonitril oder irgendeine Mischung daraus umfasst, jedoch nicht darauf beschränkt ist.
  7. Verfahren nach einem der Ansprüche 1-6, wobei die Temperatur der Cyclisierungsreaktion in dem Bereich von 60 °C - 150 °C liegt.
  8. Verfahren nach Anspruch 7, wobei die Temperatur der Cyclisierungsreaktion in dem Bereich von 100-140 °C, insbesondere bevorzugt von 115-125 °C liegt.
  9. Verfahren zum Herstellen von Linezolid, wobei das Linezolid aus dem Zwischenprodukt mit der Formel (I) hergestellt wird
    Figure imgb0024
     wobei die Definition der R-Gruppe gemäß Anspruch 1 ist,
    wobei das Zwischenprodukt mit der Formel (I) durch das Verfahren nach einem der Ansprüche 1-8 hergestellt wird.
  10. Verfahren nach Anspruch 9, wobei Linezolid durch die folgenden Reaktionen hergestellt wird:
    Figure imgb0025
  11. Verfahren nach Anspruch 10, wobei Linezolid durch die folgenden Reaktionen hergestellt wird:
    Figure imgb0026
EP13749142.9A 2012-02-15 2013-02-08 Verfahren zur herstellung eines linezolidzwischenprodukts Active EP2816039B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201210038198.3A CN103254148B (zh) 2012-02-15 2012-02-15 利奈唑胺中间体的制备方法
PCT/CN2013/071576 WO2013120448A1 (zh) 2012-02-15 2013-02-08 利奈唑胺中间体的制备方法

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EP2816039A1 EP2816039A1 (de) 2014-12-24
EP2816039A4 EP2816039A4 (de) 2015-07-15
EP2816039B1 true EP2816039B1 (de) 2017-04-05

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103288814B (zh) * 2012-02-24 2016-07-06 国药集团国瑞药业有限公司 一种利伐沙班中间体的制备方法
USRE47606E1 (en) * 2016-04-21 2019-09-17 Optimus Drugs Private Limited Process for the preparation of linezolid
WO2018055499A1 (en) * 2016-09-20 2018-03-29 Phalanx Labs Private Limited One pot synthesis for the preparation of substituted phthalimido oxazolidinone antibacterials and oxazolidinone antiharombotics compounds by using recyclable heterogeneous catalyst

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY115155A (en) 1993-09-09 2003-04-30 Upjohn Co Substituted oxazine and thiazine oxazolidinone antimicrobials.
HUP0004388A3 (en) * 1997-11-07 2001-10-29 Upjohn Co Process for the preparation of oxazolidinones, intermediates and preparation thereof
US6833453B2 (en) * 2000-10-17 2004-12-21 Pharmacia & Upjohn Company Methods of producing oxazolidinone compounds
DE60303167T2 (de) 2002-09-25 2006-09-14 Daiso Co., Ltd. Verfahren zur Herstellung von Glycidylphthalimid
ES2294494T3 (es) 2004-04-19 2008-04-01 Symed Labs Limited Un nuevo procedimiento para la preparacion de linezolid y compuestos relacionados.
CN1772750A (zh) * 2005-11-15 2006-05-17 郑州大学 （r）－n－（3－氟－4－吗啉苯基）－噁唑酮－5－甲基醇制备工艺
BRPI0710312A2 (pt) 2006-04-07 2011-08-09 Pfizer Prod Inc processo para preparar linezolida
EP2354128A1 (de) * 2010-02-10 2011-08-10 Sandoz Ag Verfahren zur Herstellung von Rivaroxaban
CA2798101A1 (en) * 2010-04-30 2011-11-03 Indiana University Research And Technology Corporation Processes for preparing linezolid
CN102250076A (zh) * 2011-05-27 2011-11-23 横店集团家园化工有限公司 一种利伐沙班中间体及利伐沙班的制备方法
CN103288814B (zh) * 2012-02-24 2016-07-06 国药集团国瑞药业有限公司 一种利伐沙班中间体的制备方法
JP2015514114A (ja) * 2012-04-06 2015-05-18 インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーションＩｎｄｉａｎａ Ｕｎｉｖｅｒｓｉｔｙ Ｒｅｓｅａｒｃｈ Ａｎｄ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏｒｐｏｒａｔｉｏｎ リバーロキサバンを調製するためのプロセス
CN102702125B (zh) * 2012-05-10 2014-09-03 浙江工业大学 一种利奈唑胺的化学合成方法

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CN103254148B (zh) 2016-04-13
CN103254148A (zh) 2013-08-21
JP5938109B2 (ja) 2016-06-22
US20150011757A1 (en) 2015-01-08
JP2015506992A (ja) 2015-03-05
EP2816039A4 (de) 2015-07-15
EP2816039A1 (de) 2014-12-24
US9434702B2 (en) 2016-09-06
WO2013120448A1 (zh) 2013-08-22

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